Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal cancers, with limited therapeutic options and a dismal prognosis. A critical driver of its progression is mutant p53 (mutp53), which alters the tumor microenvironment (TME) by influencing crucial pro-tumoral signaling factors. Given the potential of secretome profiling to reveal novel biomarkers and druggable targets, we investigated the role of the mutp53-driven secretome in PDAC cells and its implications for disease progression. Through mass-spectrometry (MS) analysis, we identified a set of secreted proteins modulated by mutp53, with the nuclear high mobility group A1 (HMGA1) serving as a central regulator. HMGA1 is a transcription factor involved in several cellular processes and found to be upregulated in different tumors, but its extracellular role in cancer remains largely unexplored. We demonstrate that mutp53-driven HMGA1 secretion promotes PDAC cell hyperproliferation, where HMGA1 deficiency significantly impairs tumor growth highlighting a critical role of this protein in tumor aggressiveness. Notably, we discovered that chemotherapy enhances HMGA1 secretion specifically in TP53-mutant PDAC cells through a mechanism dependent on Casein Kinase 2 (CK2) activity. To unravel the downstream oncogenic signaling triggered by secreted HMGA1, we conducted phosphoproteomic analysis, identifying hyperphosphorylation of Nucleophosmin 1 (NPM1), as a pivotal event that further amplifies tumor cell proliferation. Collectively, our findings reveal that a panel of chemotherapeutic agents stimulate a novel mutp53-dependent CK2-HMGA1-NPM1 axis that fuels PDAC proliferation in an autocrine/paracrine manner. Targeting this pathway at multiple levels emerges as a promising therapeutic strategy to counteract mutp53-driven tumor progression and improve patient outcomes.
© 2025. The Author(s).